Solid tumors are frequently associated with increased bone resorption and hypercalcemia. In addition to hypercalcemia, the clinical consequences include intractable bone pain and pathological fracture. Moreover, once tumors metastasize to bone, they are no loner curable using current therapeutic approaches. From our observations and those of others, it is clear that the factors responsible for the increase in bone resorption associated with malignant disease are heterogeneous. Our approach is to identify the tumor derived factors which cause this increase in osteoclastic bone resorption using an in vitro bioassay for bone resorption. We plan to characterize the bone resorbing factors produced by three tumors associated with hypercalcemia, the rat Leydig tumor, the hypercalcemic variant of the Walker 256 rat breast tumor and the BEN tumor, a human squamous cell carcinoma of the lung. The specific studies involve: 1. purification of the bone resorbing factor(s) responsible for hypercalcemia. 2. purification of the tumor derived transforming growth factors which are related to these bone resorbing factors and characterization of their interrelationships, and 3. purification of the parathyroid hormone-like factors associated with hypercalcemia and determination of the relationship of these PTH like factors to the bone resorbing factor and to the transforming growth factors. Our hope is that these studies wll clarify the mechanisms by which tumor cells increase osteoclastic bone resorption and eventually lead to specific forms of therapy designed to prevent or inhibit bone destruction which is associated with malignant disease.